We have undertaken a study to identify critical genetic events in the pathogenesis of human cancer. We have currently focused our research efforts on studying the mechanism and implication of inactivation of the retinoblastoma (Rb) gene in human cancer. Our recent findings are as follows: 1) essentially all small cell lung cancer tumors have absent or aberrant Rb protein products; 2) we have identified and characterized a series Rb mutants (defective in phosphorylation and oncoprotein binding); 3) we are investigating the possibility of these Rb mutants to function as transforming genes (dominant negative effect); 4) we have successfully transfected a wild-type or mutant Rb gene in a SCLC cell line to study its biological effect; 5) we are using our Rb open reading frame reagents to identify putative cellular proteins that normally interact with the Rb protein and presumably modulate its growth inhibitory effect; and 6) we have generated a large number of in vitro Rb mutant proteins to characterize different functional domains of this protein. In addition, we continue to maintain a research effort studying mechanisms of L-myc gene activation. We have identified a 200 Kd cellular protein that binds to a specific region of the L-myc protein and we are currently attempting to clone this protein. Further we have preliminary evidence that the Rb tumor suppressor gene may also bind to the L-myc protein as well.